Clinical outcomes trials to assess therapeutic interventions in post-mastectomy and other forms of lymphedema.

Clinical Trials

Biomarkers for the Detection of Lymphatic InsufficiencyRecruiting

Acquired lymphedema is a disease that causes chronic swelling of the limb(s). It is
frequently under-recognized or misdiagnosed. This study is designed to lead to the
development of an accurate, noninvasive, blood test to allow testing for lymphedema.

The purpose of the National Lymphatic Disease and Lymphedema Registry is to collect health
information in order to study the disease classification, natural history, and impact of
Lymphatic Disease, Lymphedema and Related Disorders and its treatments and medical outcomes.

The purpose of the National Breast Cancer Lymphedema Registry is to collect health
information in order to study the lymphedema as a complication of breast cancer treatment.
The investigators hope to learn whether early diagnosis will help to prevent lymphedema or,
if it does occur, to reduce the severity.

Ubenimex in Adult Patients With Lymphedema of The Lower Limb (ULTRA)Recruiting

Leukotriene B4 (LTB4) inhibits lymphangiogenesis in the mouse tail model of lymphedema and is
elevated in tissue in patients with lymphedema. Ubenimex is an inhibitor of leukotriene A4
hydrolase (LTA4H), the biosynthetic enzyme for LTB4. This proof-of-concept study is designed
as a randomized, double-blind, placebo-controlled study comparing ubenimex at 150 mg, 3 times
daily (total daily dose of 450 mg) with placebo for 6 months treatment period in patients
with leg lymphedema. The primary objectives for the study are:
- To evaluate the efficacy of ubenimex in patients with leg lymphedema
- To evaluate the safety and tolerability of ubenimex in patients with leg lymphedema

To better understand the mechanisms leading to lymphedema development in breast cancer
survivors, and the implications for potential innovative approaches to the screening,
prevention and treatment of this condition.

Stanford is currently not accepting patients for this trial.For more information, please contact Anne Marie Vaillant-Newman, (650) 498 - 4460.

Lymphedema Prophylaxis in Breast Cancer Survivors Who Show Early Evidence of High-risk StatusNot Recruiting

To compare the effectiveness of usual treatments for lymphedema [massage and elastic
compression sleeve, instituted at-risk and before the development of swelling (lymphedema)],
compared to the use of a newly-marketed device, the Flexitouch, which electronically
simulates the effect of massage upon lymph flow.

Stanford is currently not accepting patients for this trial.For more information, please contact Les Roche, RN, 650-724-5913.

This phase 1-2 trial studies the side effects and the best dose of recombinant human
hyaluronidase and to see how well it works in treating lymphedema in patients with cancer.
Recombinant human hyaluronidase (r-hu-hyaluronidase, rHuPH20) may reduce limb edema size in
patients with lymphedema.

Stanford is currently not accepting patients for this trial.For more information, please contact Les Roche, 650-723-1396.

The GORE Viabahn Endoprosthesis for the Treatment of Venous Occlusions and StenosesNot Recruiting

To study the safety and efficacy of drug coated stents for the treatment of venous occlusions
and stenoses in the lower extremity. The use of the device for the treatment of peripheral
arterial disease is approved by the FDA, however, the use of the device in venous occlusions
and stenoses, although performed by some practitioners, has not yet been studied in detail.

Stanford is currently not accepting patients for this trial.For more information, please contact Kamil Unver, 650-725-9810.

Abstract

Patients with lymphedema suffer lifelong swelling and recurrent cellulitis despite use of complete decongestive therapy. Pneumatic compression devices (PCDs), including non-programmable and programmable devices that meet individual patient needs, support long term self-care in the home. Yet, to date, no direct comparison of their relative benefits has been available.Patients who acquired either a non-programmable device (NP-PCD) or a dynamic pressure programmable device (P-PCD; Flexitouch(®) ) were evaluated to compare associated clinical and health utilization outcomes pre/post-device acquisition.Retrospective analysis of de-identified administrative claims from 2007 through 2013 of a large United States insurer. The study populations were defined pre hoc as distinct cancer- and non-cancer-related lymphedema cohorts. Outcome variables included rates of lymphedema-related cellulitis, manual therapy use, outpatient services, and inpatient hospitalizations. Multivariate regression analysis was performed to: (1) compare outcomes for the 12 months pre- and post-device acquisition and (2) compare these two device types for their treatment-associated benefits.The sample consisted of 1,013 NP-PCD and 718 P-PCD recipients. Compared with the NP-PCD group, P-PCD patients' baseline cellulitis rate was higher, while their post-device cellulitis rate was lower. In the cancer cohort, the NP-PCD group had a 53% reduction in episodes of cellulitis (from 17.9% to 8.5%), compared to a greater 79% reduction in the P-PCD group (from 23.7% to 5.0%) (p<0.001). In the non-cancer cohort, the P-PCD group also experienced a larger 76% decline (from 31.7% to 7.4%) vs. 54% decline (from 22.9% to 10.6%) in cellulitis rates (p=0.003). Outpatient service use reduced in both device groups, with greater reductions observed in P-PCD group. Both device groups experienced reductions in manual therapy use. Inpatient hospitalizations were largely stable with reductions observed only in the non-cancer cohort of the P-PCD group.P-PCD receipt was associated with superior lymphedema-related health outcomes and reductions in cellulitis. This article is protected by copyright. All rights reserved.

Abstract

Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

Abstract

Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.

Abstract

Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis and childhood onset of facial and four limb lymphoedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant dehydrated hereditary stomatocytosis and non-immune hydrops of unknown aetiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.

Abstract

Lymphangiomatosis is an uncommon proliferative disorder of the lymphatic vasculature whose etiology remains poorly understood. The lymphangiomatosis spectrum encompasses a remarkable heterogeneity in its potential presentation, including micro- and macrocystic isolated lymphatic malformations, thoracic and intraabdominal diffuse lymphangiomatosis, and osseous and soft-tissue presentations known as Gorham-Stout disease. Recent therapeutic advances are empirical in nature or, at best, inferential, reflecting the scanty availability of laboratory-based model systems for the mechanistic study of this disease. Several promising model systems are reviewed here. The laboratory investigation of lymphangiomatosis will likely continue to benefit from the remarkable growth of insights into the mechanisms of lymphangiogenesis and vascular development.

Abstract

Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4(+) cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4(+) inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4(+) cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.

Abstract

The lymphatic system is fundamentally important to cardiovascular disease, infection and immunity, cancer, and probably obesity--the four major challenges in healthcare in the 21st century. This Review will consider the manner in which new knowledge of lymphatic genes and molecular mechanisms has demonstrated that lymphatic dysfunction should no longer be considered a passive bystander in disease but rather an active player in many pathological processes and, therefore, a genuine target for future therapeutic developments. The specific roles of the lymphatic system in edema, genetic aspects of primary lymphedema, infection (cellulitis/erysipelas), Crohn's disease, obesity, cancer, and cancer-related lymphedema are highlighted.

Abstract

Apelin and its cognate receptor Aplnr/Apj are essential for diverse biological processes. However, the function of Apelin signaling in lymphatic development remains to be identified, despite the preferential expression of Apelin and Aplnr within developing blood and lymphatic endothelial cells in vertebrates. In this report, we aim to delineate the functions of Apelin signaling during lymphatic development.We investigated the functions of Apelin signaling during lymphatic development using zebrafish embryos and found that attenuation of Apelin signaling substantially decreased the formation of the parachordal vessel and the number of lymphatic endothelial cells within the developing thoracic duct, indicating an essential role of Apelin signaling during the early phase of lymphatic development. Mechanistically, we found that abrogation of Apelin signaling selectively attenuates lymphatic endothelial serine-threonine kinase Akt 1/2 phosphorylation without affecting the phosphorylation status of extracellular signal-regulated kinase 1/2. Moreover, lymphatic abnormalities caused by the reduction of Apelin signaling were significantly exacerbated by the concomitant partial inhibition of serine-threonine kinase Akt/protein kinase B signaling. Apelin and vascular endothelial growth factor-C (VEGF-C) signaling provide a nonredundant activation of serine-threonine kinase Akt/protein kinase B during lymphatic development because overexpression of VEGF-C or apelin was unable to rescue the lymphatic defects caused by the lack of Apelin or VEGF-C, respectively.Taken together, our data present compelling evidence suggesting that Apelin signaling regulates lymphatic development by promoting serine-threonine kinase Akt/protein kinase B activity in a VEGF-C/VEGF receptor 3-independent manner during zebrafish embryogenesis.

Abstract

Lymphedema is a common complication of cancer therapeutics; its prevalence, treatment outcomes, and costs have been poorly defined. The objective of this study was to examine lymphedema prevalence among cancer survivors and to characterize changes in clinical outcomes and costs associated with a defined therapeutic intervention (use of a pneumatic compression devices [PCD]) in a representative, privately insured population.Retrospective analysis of de-identified health claims data from a large national insurer for calendar years 2007 through 2013. Patients were required to have 12 months of continuous insurance coverage prior to PCD receipt (baseline), as well as a 12-month follow-up period. Analyses were performed for individuals with cancer-related lymphedema (n = 1,065). Lymphedema prevalence was calculated: number of patients with a lymphedema claim in a calendar year divided by total number of enrollees. The impact of PCD use was evaluated by comparing rates of a pre-specified set of health outcomes and costs for the 12 months before and after, respectively, PCD receipt. Lymphedema prevalence among cancer survivors increased from 0.95% in 2007 to 1.24% in 2013. PCD use was associated with decreases in rates of hospitalizations (45% to 32%, p<0.0001), outpatient hospital visits (95% to 90%, p<0.0001), cellulitis diagnoses (28% to 22%, p = 0.003), and physical therapy use (50% to 41%, p<0.0001). The average baseline health care costs were high ($53,422) but decreased in the year after PCD acquisition (-$11,833, p<0.0001).Lymphedema is a prevalent medical condition that is often a defining attribute of cancer survivorship. The problem is associated with high health care costs; Treatment (in this instance, use of PCD) is associated with significant decreases in adverse clinical outcomes and costs.

Abstract

Primary lymphedema can be managed effectively as a form of chronic lymphedema by a sequenced and targeted treatment and management program based around a combination of Decongestive Lymphatic Therapy (DLT) with compression therapy, when the latter is desired as an adjunct to DLT. Treatment in the maintenance phase should include compression garments, self-management, including self-massage, meticulous personal hygiene and skin care, in addition to lymphtransport-promoting excercises and activities, and, if desired, pneumatic compression therapy applied in the home. When conservative treatment fails, or gives sub-optimal outcomes, the management of primary lymphedema can be improved, where appropriate, with the proper addition of surgical interventions, either reconstructive or ablative. These two surgical therapies can be more effective when fully integrated with manual lymphatic drainage (MLD)-based DLT postoperatively. Compliance with a long-term commitment to MLD/DLT and particularly compression postoperatively is a critical factor in determining the success of any new treatment strategy involving either reconstructive or palliative surgery. The future of management of primary lymphedema has never been brighter with the new prospect of gene-and perhaps stem-cell oriented management.

The Lymphatics and the Inflammatory Response: Lessons Learned from Human LymphedemaLYMPHATIC RESEARCH AND BIOLOGYRockson, S. G.2013; 11 (3): 117-120

Abstract

In lymphedema, there is a profound predisposition to infection with bacterial pathogens. It therefore seems appropriate to reconsider our unique functional definition of the lymphatic structures within a circulatory construct. While the lymphatics unquestionably fulfill a vital circulatory function, it seems more appropriate to view this complex network, comprised both of endothelial-lined vessels and of lymphoid tissue, as the nexus between the circulatory and immune systems. Viewed in this fashion, it becomes evident that the complex biology of regional lymphatic disruption is a manifestation of the interplay between these two vital bodily functions. Experimental lymph stasis in murine model has been utilized to effectively demonstrate the pathological attributes of human lymphedema, namely, inflammation, fat deposition, and fibrosis. Large-scale transcriptional corroborates the role of inflammatory mechanisms. The murine studies have set the stage for subsequent translational investigation of human lymphedema. Many of the gene expression pathways invoked by lymphedema are relevant to the inflammatory response and have provided a pragmatic approach to the successful identification of potentially relevant circulating biomarkers for human lymphedema.

Abstract

Lymphedema is a dreaded complication of cancer treatment. However, despite the fact that >5 million Americans are affected by this disorder, the development of effective treatments is limited by the fact that the pathology of lymphedema remains unknown. The purpose of these studies was to determine the role of inflammatory responses in lymphedema pathology. Using mouse models of lymphedema, as well as clinical lymphedema specimens, we show that lymphatic stasis results in a CD4 T-cell inflammation and T-helper 2 (Th2) differentiation. Using mice deficient in T cells or CD4 cells, we show that this inflammatory response is necessary for the pathological changes of lymphedema, including fibrosis, adipose deposition, and lymphatic dysfunction. Further, we show that inhibition of Th2 differentiation using interleukin-4 (IL-4) or IL-13 blockade prevents initiation and progression of lymphedema by decreasing tissue fibrosis and significantly improving lymphatic function, independent of lymphangiogenic growth factors. We show that CD4 inflammation is a critical regulator of tissue fibrosis and lymphatic dysfunction in lymphedema and that inhibition of Th2 differentiation markedly improves lymphatic function independent of lymphangiogenic cytokine expression. Notably, preventing and/or reversing the development of pathological tissue changes that occur in lymphedema may be a viable treatment strategy for this disorder.

Abstract

In our previous transcriptional profiling of a murine model, we have identified a remarkably small number of specific pathways with altered expression in lymphedema. In this investigation, we utilized microarray-based transcriptomics of human skin for an unbiased a priori prospective candidate identification, with subsequent validation of these candidates through direct serum assay. The resulting multi-analyte biomarker panel sensitively should sensitively discriminate human lymphedema subjects from normal individuals.We enrolled 63 lymphedema subjects and 27 normals in our attempt to discover protein analytes that can distinguish diseased individuals from controls. To minimize technical and biologically irrelevant variation, we first identified potential candidates by performing transcriptional microarray analysis on paired diseased and normal skin specimens sampled from the same individuals. We focused our attention on genes with corresponding protein products that are secreted and took these candidates forward to a protein multiplex assay applied to diseased and normal subjects. We developed a logistic regression-based model on an eventual group of six proteins and validated our system on a separate cohort of study subjects. The area under the receiver operating characteristic curve was calculated to be 0.87 (95% CI : 0.75 to 0.97).We have developed an accurate bioassay utilizing proteins representing four central pathogenetic modalities of the disease: lymphangiogenesis, inflammation, fibrosis, and lipid metabolism, suggesting that these proteins are directly related to the pathogenesis of the tissue pathology in lymphatic vascular insufficiency. Further studies are warranted to determine whether this newly-identified biomarker panel will possess utility as an instrument for in vitro diagnosis of early and latent disease; the ultimate applicability to risk stratification, quantitation of disease burden, and response to therapy can easily be envisioned.

Abstract

Published data regarding the effect of concomitant clopidogrel and proton pump inhibitor (PPI) therapy on cardiovascular outcomes have been conflicting.To perform an updated meta-analysis in order to determine changes in risk differences (RD) between primary and secondary outcome analyses.Primary analysis was based on definite vascular outcomes, including all cause mortality, cardiac death, myocardial infarction, and/or stroke. Secondary analysis also incorporated probable cardiac events, which included re-hospitalization for cardiac symptoms or revascularization procedures. RD were combined using a random-effects model.We reviewed 1,204 publications of which 26 studies (16 published articles, 10 abstracts) met inclusion criteria. The meta-analysis of outcomes from the two randomized controlled trials did not show an increased risk (RD 0.0, 95% CI -0.01, 0.01) for adverse outcomes. The meta-analysis of primary outcomes showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies. The meta-analysis for secondary outcomes yielded a RD of 0.02 (95% CI 0.01-0.04) based on 19 published papers and abstracts. When primary and secondary outcomes were combined, the meta-analysis for published papers yielded an overall RD of 0.05 (95% CI 0.03-0.06).In patients using concomitant clopidogrel and PPI therapy, the risk of adverse cardiac outcomes was 0% based on data from well-controlled randomized trials. Data from retrospective studies and the addition of probable vascular events significantly increased the RD estimates, likely due to lack of adjustment for potential confounders.

Abstract

OPINION STATEMENT: The past decade has produced an explosion of insights into lymphatic vascular development and structural biology and, in parallel, into the function of the lymphatics in health and in disease. In lymphedema, there is a spectrum that extends from primary (heritable) to acquired causes of disease. The diagnosis of lymphatic edema implicates a very specific treatment approach that is predicated upon the favorable impact of physiotherapy upon lymph flow and protein clearance from the edematous zones of the body. The recognition of the unique biology that accompanies lymphatic causes of edema has stimulated new research directions that are likely to translate into exciting new pharmacologic and molecular approaches to diagnosis and treatment.

Abstract

The systematic study of focused animal models has produced an explosion of information regarding the mechanisms governing lymphatic development and the diseases associated with lymphatic dysfunction. Nevertheless, the pathogenesis of systemic lymphangiomatosis has, thus far, eluded mechanistic comprehension. In this review, recent molecular advances in lymphatic vascular development are considered within the context of the animal models that have produced evolving insights. The emerging role of the zebrafish within lymphatic investigation is discussed. Specific models of the human disease pathology are considered in detail. While much has been learned about the molecular framework that surrounds normal lymphatic vascular development, the defect responsible for systemic lymphangiomatosis remains elusive. Development of more robust, recapitulative models will also be invaluable to investigate new and emerging therapeutics for the often devastating disease of systemic lymphangiomatosis.

Abstract

Lymphedema is a complication of cancer treatment occurring in approximately 50% of patients who undergo lymph node resection. Despite its prevalence, the etiology of this disorder remains unknown. In this study, we determined the effect of soft tissue fibrosis on lymphatic function and the role of transforming growth factor (TGF)-β1 in the regulation of this response. We determined TGF-β expression patterns in matched biopsy specimens collected from lymphedematous and normal limbs of patients with secondary lymphedema. To determine the role of TGF-β in regulating tissue fibrosis, we used a mouse model of lymphedema and inhibited TGF-β function either systemically with a monoclonal antibody or locally by using a soluble, defective TGF-β receptor. Lymphedematous tissue demonstrated a nearly threefold increase in the number of cells that stained for TGF-β1. TGF-β inhibition markedly decreased tissue fibrosis, increased lymphangiogenesis, and improved lymphatic function compared with controls. In addition, inhibition of TGF-β not only decreased TGF-β expression in lymphedematous tissues, but also diminished inflammation, migration of T-helper type 2 (Th2) cells, and expression of profibrotic Th2 cytokines. Similarly, systemic depletion of T-cells markedly decreased TGF-β expression in tail tissues. Inhibition of TGF-β function promoted lymphatic regeneration, decreased tissue fibrosis, decreased chronic inflammation and Th2 cell migration, and improved lymphatic function. The use of these strategies may represent a novel means of preventing lymphedema after lymph node resection.

Current concepts and future directions in the diagnosis and management of lymphatic vascular diseaseVASCULAR MEDICINERockson, S. G.2010; 15 (3): 223-231

Abstract

Despite the central, complex role for the lymphatic system in the maintenance of human health, the biology of this important and complex vasculature has been relatively under-investigated. However, the last decade has witnessed a substantial growth in the elucidation of lymphatic structural biology and the function of this system in health and in disease. These newly gained insights can be used to formulate our evolving concepts about the diagnostic and therapeutic approaches to patients with lymphatic vascular disorders. In lymphedema, there is a spectrum of disease that extends from primary (heritable) to secondary (acquired) causes. Once detected, the presence of lymphatic edema mandates very specific modalities of intervention, predominated by physiotherapeutic techniques. In addition, a physiological basis for adjunctive, intermittent pneumatic compression has been established, and these modalities may be indicated in selected patient populations. The acknowledgement of a unique biology in lymphatic edemas is, increasingly, guiding research efforts within this field. Increasing investigative attention is being directed toward animal models of lymphatic vascular disease. As insight into the complex biology of the lymphatic vasculature continues to expand through focused biomedical investigation, the translation of these mechanistic insights into targeted, rationally conceived therapeutics will become increasingly feasible.

Causes and consequences of lymphatic diseaseConference on Lymphatics in the Digestive System - Physiology, Health, and DiseaseRockson, S. G.WILEY-BLACKWELL.2010: E2–E6

Abstract

The visceral manifestations of lymphatic disorders (lymphangiomatosis and lymphangiectasia) are particularly severe. Any pathology of the lymphatic vasculature, whether superficial or internal, regional, or systemic, is predominated by the appearance of lymphedema, the characteristic form of tissue edema that occurs when lymphatic dysfunction supervenes. Disease manifestations may include dysregulation of body fluid homeostasis, immune traffic impairment, and disturbances of lipid and protein reabsorption from the gut lumen. The appearance of lymphatic edema invokes complex biological alterations. Many of these changes seem to relate uniquely to chronic lymphatic edema, including a profound stimulus to collagen and adipose deposition. Despite the recent advances in our understanding of these disorders, substantial knowledge gaps remain; these gaps inhibit our ability to accurately identify, categorize, treat, and prevent these diseases. Future diagnostic, therapeutic, and reproductive decisions for affected individuals require an accurate knowledge of the clinical and laboratory presentation, mode of inheritance, treatment response, outcomes, and prognosis.

Abstract

In a widely employed murine tail model of human acquired lymphedema, we have previously observed that, distal to the site of experimental lymphatic ablation, there is immunohistochemical evidence of a profound increase in cutaneous lymphatic vessel number and size that normalizes after VEGF-C administration.In order to investigate the mechanistic basis of the lymphatic microvascular remodeling, we have studied the lymphedematous responses to VEGF-C after co-administration of systemic VEGFR-3 neutralizing antibody. We have also undertaken genome-wide whole-tissue transcriptional profiling of lymphedematous tissues before and after exogenous VEGF-C administration.We provoked postsurgical lymphedema in the mouse tail model and assessed the effects of exogenously administered human recombinant VEGF-C in the presence of a monoclonal anti-VEGFR-3 antibody. Polyclonal IgG was administered to a series of control subjects. Microvascular lymphatic remodeling was assessed through quantitative and qualitative anti-LYVE1 immunohistochemistry. Genome-wide transcriptional profiling was performed in whole skin derived from lymphedema with and without exogenous VEGF-C administration. Normal mice and surgical shams served as controls.In the presence of the monoclonal anti-VEGFR-3 neutralizing antibody, positive lymphatic microvascular remodeling in lymphedematous skin is nearly completely abrogated. Furthermore, the therapeutic impact of added VEGF-C is markedly attenuated, as is the ability of the growth factor to ameliorate tissue edema. Transcriptional profiling of the VEGF-C responses in treated lymphedema reveals a very restricted list of genes whose expression is upregulated in lymphedema and re-normalized following VEGF-C treatment.The postsurgical murine tail model of lymphedema closely simulates attributes of human lymphedema. The current series of investigations underscores the utility of the murine tail model to the preclinical and translational investigation of lymphedema. The derived insights continue to focus favorably upon the central role of the VEGFR-3 receptor and its ligands in the development and therapeutic resolution of lymphedema. Whole tissue transcriptional profiling continues to shed light on disease mechanisms and potential future targets for therapeutic intervention.

Abstract

Sadly, the subject of lymphatic vascular insufficiency continues to engender relative neglect by health care professionals, which represents a source of frustration and fear among patients. A re-consideration of the unique, complex biology of lymphatic vascular disorders has the capacity both to reinvigorate interest and facilitate the implementation of the correct, existing treatment interventions for individuals affected by these disease states. While most of this complex lymphatic biology remains somewhat elusive, growing insights into the molecular mechanisms of lymphatic development and repair have been instructive. Present and future considerations in lymphedema diagnosis and management must acknowledge the unique tissue biology of this disorder. Many changes are unique to the lymphatic mechanisms of chronic edema. The profound stimulus to collagen deposition in the integument seems to be unique to chronic lymphatic edema, although this biology remains largely unexplicated. Several lines of evidence also suggest that lymphatic function has a unique and important influence upon adipose biology. Molecular investigation of murine models of human acquired lymphedema are beginning to shed light on these processes. Such focused mechanistic, approaches to the study of lymphedema and other lymphatic diseases are vital, as we attempt to expand our insights into the complex biology of lymphedema and its potential responsiveness to pharmacologic control and molecular intervention, prevention, and reversal.

Abstract

The use of guideline-recommended secondary prevention measures is essential for reducing the risk of subsequent events and mortality in patients who have survived an acute atherothrombotic event or have peripheral arterial disease. Although initial hospitalization provides an ideal environment to initiate such therapies, implementation of effective longterm prevention strategies is hindered by the absence of a systematic approach. In general, evidence-based clinical practice guidelines recommend antiplatelet therapy as a cornerstone of post-discharge secondary prevention, in addition to preventive measures targeting risk factors such as hypertension, dyslipidemia, cigarette smoking, and physical inactivity. Observational data indicate that, although there has been improvement over time, current utilization of guideline-recommended post-discharge treatment remains suboptimal. Recognizing the importance of a systematic approach to discharge planning, numerous hospital-based initiatives have been established. In conjunction with effective lines of communication between hospital and primary care teams, initiation of the most effective secondary prevention strategy at the time of hospital discharge will help to ensure optimal long-term management of patients after an atherothrombotic event.

The role of the lymphatic circulation in the natural history and expression of cardiovascular diseaseINTERNATIONAL JOURNAL OF CARDIOLOGYNakamura, K., Rockson, S. G.2008; 129 (3): 309-317

Abstract

The lymphatic vasculature is essential to fluid, protein and cellular transport, and to immune responsiveness. The last decade has witnessed a virtual renaissance of investigation into the function of the lymphatic microvasculature, prompting re-consideration of its role in the genesis and progression of cardiovascular pathology. The lymphatic microvasculature of the heart and vascular wall likely participate in atherogenesis, myocardial infarction, congestive heart failure, and cardiac transplantation. Intensive exploration of lymphatic mechanisms of cardiovascular disease is likely to lead to enhanced insights and novel therapeutic approaches.

Diagnosis and management of lymphatic vascular diseaseJOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGYRockson, S. G.2008; 52 (10): 799-806

Abstract

The lymphatic vasculature is comprised of a network of vessels that is essential both to fluid homeostasis and to the mediation of regional immune responses. In health, the lymphatic vasculature possesses the requisite transport capacity to accommodate the fluid load placed upon it. The most readily recognizable attribute of lymphatic vascular incompetence is the presence of the characteristic swelling of tissues, called lymphedema, which arises as a consequence of insufficient lymph transport. The diagnosis of lymphatic vascular disease relies heavily upon the physical examination. If the diagnosis remains in question, the presence of lymphatic vascular insufficiency can be ascertained through imaging, including indirect radionuclide lymphoscintigraphy. Beyond lymphoscintigraphy, clinically-relevant imaging modalities include magnetic resonance imaging and computerized axial tomography. The state-of-the-art therapeutic approach to lymphatic edema relies upon physiotherapeutic techniques. Complex decongestive physiotherapy is an empirically-derived, effective, multicomponent technique designed to reduce limb volume and maintain the health of the skin and supporting structures. The application of pharmacological therapies has been notably absent from the management strategies for lymphatic vascular insufficiency states. In general, drug-based approaches have been controversial at best. Surgical approaches to improve lymphatic flow through vascular reanastomosis have been, in large part, unsuccessful, but controlled liposuction affords lasting benefit in selected patients. In the future, specifically engineered molecular therapeutics may be designed to facilitate the controlled regrowth of damaged, dysfunctional, or obliterated lymphatic vasculature in order to circumvent or mitigate the vascular insufficiency that leads to edema and tissue destruction.

Abstract

Lymphatic disease is quite prevalent, and often not well clinically characterized. Beyond lymphedema, there is a broad array of human disease that directly or indirectly alters lymphatic structure and function. The symptomatic and objective presentation of these patients can be quite diverse. In this review, we have attempted to provide a systematic overview of the subjective and objective spectrum of lymphatic disease, with consideration of all of the categories of disease that primarily or secondarily impair the functional integrity of the lymphatic system. Lymphedema is discussed, along with chromosomal disorders, lymphangioma, infectious diseases, lymphangioleiomyomatosis, lipedema, heritable genetic disorders, complex vascular malformations, protein-losing enteropathy, and intestinal lymphangiectasia.

Abstract

The convergence of multiple disciplines upon the study of the lymphatic vasculature has invigorated a renaissance of research, using powerful investigative tools and an exponential growth of interest in this historically underappreciated system. Fundamental discoveries in lymphatic development have yielded relevant animal models for vexing clinical diseases that suffer from nonexistent of minimally effective treatments. Inherited and acquired lymphedema represent the current crux of research efforts to identify potential molecular therapies born from these early discoveries. The importance of the lymphatic system is, however, not limited to lymphedema but encompasses a diverse spectrum of human disease including inflammation and cancer metastasis. As the lymphatic vasculature continues to benefit from fruits of biomedical investigation, translation of mechanistic insights into targeted, rationally-conceived therapeutics will be become a reality.

Abstract

Gorham's disease, also known as massive osteolysis, Gorham-Stout disease, vanishing bone disease, or, phantom bone disease is a rare disorder of the musculoskeletal system. The disease is characterized by osteolysis in bony segments, with localized proliferation of lymphatic channels. The presence of abundant, leaky systemic lymphatic vessels is often accompanied by chylous ascites. There is no standardized treatment available for Gorham's disease, and its molecular mechanisms remain unclear. Future strategies for understanding Gorham's disease should emphasize its apparent identity as a disease of disordered lymphangiogenesis. Breakthroughs in lymphatic research have identified several lymphangiogenic pathways that may play a relevant role in Gorham's disease.

Abstract

Lymphedema is a complex, regional edematous state that ensues when lymph transport is insufficient to maintain tissue homeostasis. The disorder is remarkably prevalent, but the population implications of lymphatic dysfunction are not well-studied. Prevalence estimates for lymphedema are relatively high, yet its prevalence is likely underestimated. The ability to estimate the burden of disease poses profound implications for current and future lymphedema patients, but the challenge to correctly surmise the incidence and prevalence of lymphedema is complex and the relevant medical literature is scanty. In the absence of the highly desired, prospectively designed and rigorously performed relevant epidemiologic studies, it is instructive to look at the existing studies of lymphedema disease burden. In the current review, the extant literature is examined in the context of the disease setting in which tissue edema is encountered. Incidence or prevalence estimates are provided or inferred, and, where feasible, the size of the subject population is also identified. It is extremely attractive to contemplate that future approaches will entail formal, prospectively designed studies to objectively quantitate incidence and prevalence statistics for individual categories, as well as for the global lymphedema population.

Abstract

The development of animal model systems for the study of the lymphatic system has resulted in an explosion of information regarding the mechanisms governing lymphatic development and the diseases associated with lymphatic dysfunction. Animal studies have led to a new molecular model of embryonic lymphatic vascular development, and have provided insight into the pathophysiology of both inherited and acquired lymphatic insufficiency. It has become apparent, however, that the importance of the lymphatic system to human disease extends, beyond its role in lymphedema, to many other diverse pathologic processes, including, very notably, inflammation and tumor lymphangiogenesis. Here, we have undertaken a systematic review of the models as they relate to molecular and functional characterization of the development, maturation, genetics, heritable and acquired diseases, and neoplastic implications of the lymphatic system. The translation of these advances into therapies for human diseases associated with lymphatic dysfunction will require the continued study of the lymphatic system through robust animal disease models that simulate their human counterparts.

Abstract

Patients with a history of acute coronary syndrome are particularly susceptible to further vascular or ischemic events. Effective secondary prevention following acute coronary syndrome requires multiple medications targeting the different mechanisms of atherothrombosis. The 2002 American College of Cardiology/American Heart Association guidelines for the management of unstable angina and non ST-segment myocardial infarction and the 2004 guidelines for ST-segment myocardial infarction assign priority to the long-term administration of four critical classes of drugs: antiplatelet agents, in particular aspirin and clopidogrel, beta-blockers, angiotensin-converting enzyme inhibitors, and statins.Despite clinical trial evidence demonstrating their ability to reduce cardiovascular morbidity and mortality, available preventive pharmacotherapies remain underutilized. Suboptimal compliance with current recommendations, as with other management guidelines, arises from a host of entrenched physician, patient, and system-related factors. Optimal management of acute coronary syndrome acknowledges a continuum of care in which acute stabilization represents a single important component. Early, in-hospital implementation of secondary preventive measures reinforces the continuum of care approach, promoting a successful transition from treatment to prevention, inpatient to outpatient management, and, when appropriate, subspecialist to generalist care.

Abstract

Milroy disease, also known as primary congenital lymphedema, is a hereditary form of lymphedema with autosomal dominant inheritance. Individuals with Milroy disease are typically characterized by congenital onset of lymphedema of the lower limbs due to hypoplasia of the lymphatic vessels. The genetic basis of most cases of Milroy disease has not been established, although mutations in the vascular endothelial growth factor receptor VEGFR3 (FLT-4) are responsible for some cases with 17 mutations described to date. In this report, we describe a novel VEGFR3 mutation in exon 22 in a four-generation family in which congenital lymphedema segregates in an autosomal dominant manner. In addition to lymphedema, affected family members had other clinical manifestations associated with Milroy disease including hydrocele, ski jump toenails, large caliber veins, and subcutaneous thickening. We screened VEGFR3 for mutations which revealed a novel 3059A>T transversion in exon 22 resulting in Q1020L missense mutation in the second tyrosine kinase domain of VEGFR3. This mutant allele segregated with lymphedema among affected individuals with incomplete penetrance. This is the first report of an exon 22 mutation in Milroy disease.

Abstract

Current hospital practice involves protracted observation of chest-pain patients to rule out myocardial infarction. Concurrent measurement of multiple biomarkers may increase sensitivity and make rapid diagnosis feasible.We sought to determine the optimal biomarker strategy for highly sensitive, early diagnosis of myocardial injury.A prospective evaluation of 171 acute coronary syndrome patients admitted to a single university medical center was performed. Blood tests for creatine kinase (CK), CK myocardial band isoenzyme (CK-MB), and troponin T were obtained at 0, 3, 6, 8, and 16 hours after presentation to the emergency department. Myocardial injury was defined as a troponin T level of >or=0.03 ng/mL.Troponin T had sensitivities of 79.7%, 95.7%, and 98.4% at the time of initial presentation, 3 and 6 hours after presentation, respectively. Using a combination of troponin T and CK-MB relative index, sensitivity on presentation was increased to 90.6%. The sensitivity was improved to 97.9% and 100% at 3 and 6 hours, respectively.This study demonstrates that the diagnosis of myocardial injury can be accurately excluded within 6 hours of admission with high sensitivity using troponin T. The combination of troponin T and CK-MB relative index provided the largest improvement in diagnostic sensitivity at patient arrival. These results support the feasibility of rapid, efficient triage for the emergent presentation of patients with chest pain.

Abstract

Substantial advances have accrued over the last decade in the identification of the processes that contribute to lymphatic vascular development in health and disease. Identification of distinct regulatory milestones, from a variety of genetic models, has led to a stepwise chronology of lymphatic development. Several molecular species have been identified as important tissue biomarkers of lymphatic development and function. At present, vascular endothelial growth-factor receptor (VEGFR)-3/VEGF-C/VEGF-D signaling has proven useful in the identification of clinical lymphatic metastatic potential and the assessment of cancer prognosis. Similar biomarkers, to be utilized as surrogates for the assessment of inherited and acquired diseases of the lymphatic circulation, are actively sought, and will represent a signal advance in biomedical investigation.

Abstract

Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic.We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response.We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.

Abstract

Aggressively applied decongestive measures (ie, manual lymphatic drainage, low-stretch bandaging, exercise, skin care, application of compressive elastic garments) are the mainstay of lymphatic therapy. Therapeutic regimens should differentiate between the sequential goals of acute volume reduction and maintenance of limb volume. Elastic garments should not be employed until maximal volume reduction has been attained through decongestive lymphatic techniques. It is my opinion that use of intermittent pneumatic compression devices can play an important adjunctive role to decongestive lymphatic therapy but should not be substituted for these techniques. At this time, I am not inclined to use pharmacologic therapy in these patients but anxiously await the results of studies that might demonstrate efficacy for molecular approaches. Surgical intervention is reserved for a small number of well-selected patients. Liposuction for volume reduction appears to be a very promising approach for specific patients.

Abstract

Prospective investigations of complete decongestive lymphatic physiotherapy (CDPT), including manual lymphatic drainage (MLD), have validated the efficacy of these interventions for the initial reduction of edema and long-term maintenance of limb volume in lymphedema. However, CDPT demands substantial time and effort from patients to maintain these benefits; the treatments are not always well-accepted, and patients may suffer from a deterioration in quality-of-life or a time-dependent loss of initial treatment benefits. A new device designed for home use by the patient, the Flexitouch, has been developed to mechanically simulate MLD. We have undertaken a prospective, randomized, crossover study of the efficacy of the Flexitouch, when compared to massage, in the self-administered maintenance therapy of lymphedema.A prospective, randomized, crossover study of maintenance therapy was performed in 10 patients with unilateral breast cancer-associated lymphedema of the arm. Each observation phase included self-administered treatment with the Flexitouch or massage, 1 hour daily for 14 days, respectively, followed by crossover to the alternate treatment phase. Each treatment phase was preceded by a 1 week treatment washout, with use of garment only. The sequence of treatment was randomly assigned. The potential impact of treatment modality on quality of life was assessed with serial administration of the SF-36.Statistical analysis disclosed that the order of treatment had no outcome influence, permitting 10 comparisons within each treatment group. Post-treatment arm volume reduced significantly after the Flexitouch, but not after self-administered massage. The patients' mean weight decreased significantly with Flexitouch use, but not with massage. The Flexitouch device was apparently well-tolerated and accepted by patients. Serial SF-36 administration showed no deterioration in physical or psychosocial scores compared to baseline measurements; there were no statistical differences in scores when the two treatment modalities were compared.This short-term prospective evaluation of the Flexitouch suggests that the device may provide better maintenance edema control than self-adiminstered massage in breast cancer-associated lymphedema. The apparent ease of use and reliability of response to the device suggest that further broad-scale testing is warranted.

Validation of a new technique for the quantitation of edema in the experimental setting.Lymphatic research and biologyPan, D., Han, J., Wilburn, P., Rockson, S. G.2006; 4 (3): 153-158

Abstract

An inherent limitation to the study of in vivo animal models of lymphedema is the potential inaccuracy or unreliability of existing methods for the quantification of edema volume as a surrogate functional measure of lymphatic transport capacity. Circumference-based techniques have been proposed and validated as a suitable alternative to volume displacement measurements in human clinical studies; accordingly, we have elaborated a new application of this approach that can be applied to small animal studies.Acute postsurgical lymphedema was created experimentally in the murine tail. Both normal and lymphedematous murine tails were examined. Tail volume was quantitated both by water displacement and by a digital photographic technique. In selected mice, after sacrificed on postsurgical day 7, a 6 cm segment was resected from the midportion of the tail and cauterized to create a closed space. Known incremental volumes of saline (20-100 microL) were injected for subsequent digital photographic volumetry.The coefficients of variation for volume assessment by water displacement and by digital imaging were 0.08+/-0.09 and 0.01+/-0.009, respectively. The two techniques were poorly correlated: while serial water displacement analysis yielded highly variable measurements within the same tail, concurrent digital imaging of the tail circumference was quite reproducible. Furthermore, after parenteral injection of known incremental volumes of saline, the correlation between the injectate volumes and the digitally measured increases in volume was high, both in the normal and the lymphedematous tail.In the murine tail, when compared to water displacement volumetry, digital photography yields highly reproducible data. We can conclude that the lack of correlation between the two methods, with the relatively flat slope of the linear regression relationship, reflects inherent inaccuracies of the water displacement method.

Abstract

Evaluation of the efficacy of molecular treatment strategies for lymphatic vascular insufficiency requires a suitable preclinical animal model. Ideally, the model should closely replicate the untreated human disease in its pathogenesis and pathological expression.We have undertaken a study of the time course of the development and resolution of acquired, experimental lymphedema and of its responses to vascular endothelial growth factor (VEGF)-C lymphangiogenesis in the mouse tail model.We provoked post-surgical lymphedema in the mouse tail model and assessed the effects of exogenously administered human recombinant VEGF-C. Quantitative assessment of immune traffic function was performed through sequential in vivo bioluminescent imaging.In untreated lymphedema, tail edema was sustained until day 21. Exogenous administration of human recombinant VEGF-C produced a significant decrease in volume. Untreated lymphedema in the mouse tail model was characterized by the presence of dilated cutaneous lymphatics, marked acute inflammatory changes, and hypercellularity; VEGF-C produced a substantial reversion to the normal pattern, with notable regression in the size and number of cutaneous lymphatic vessels that express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). In vivo imaging confirmed the presence of an impairment of immune traffic in lymphedema that was ameliorated after VEGF-C administration.The post-surgical murine tail model of lymphedema closely simulates attributes of human lymphedema and provides the requisite sensitivity to detect therapeutically induced functional and structural alterations. It can, therefore, be used as an investigative platform to assess mechanisms of disease and its responses to candidate therapies, such as therapeutic lymphangiogenesis.

Abstract

Recently, indirect magnetic resonance lymphangiography with gadolinium (Gd) has been demonstrated to offer the potential for safe, high-resolution visualization of the lymphatic vessels, in addition to the lymph nodes. In this study, the potential utility of indirect Gd contrast magnetic resonance imaging of lymphatic vascular function was investigated in the murine tail. Functional imaging of healthy mice is contrasted with the findings in experimentally-induced lymphatic vascular insufficiency.Postsurgical lymphedema was experimentally created in the murine tail. Normal and lymphedematous mouse tails were imaged following direct subcutaneous administration of Gadolinium-DTPA, 0.1 mmol/kg. Images were obtained in axial and coronal planes with a T1-weighted spin echo inversion-recovery sequence.In the normal tail, both of the bilateral major collecting lymphatics were clearly visualized as the Gd tracer was cleared from the interstitial compartment. In contrast, the Gd tracer accumulated at the prior surgical site in the lymphedematous tail. Quantitative assessment of Gd clearance demonstrates that accumulation of Gd correlates with the impedance to lymph flow proximal to the site of surgical lymphatic ablation.Magnetic resonance is a feasible and reliable method to be applied to quantitative functional imaging of the lymphatic vasculature in experimental models of lymphedema.

Abstract

We report a case of severe digital ulcerations associated with systemic sclerosis, successfully treated with treprostinil (Remodulin). There was improvement within days of the treatment initiation; complete healing was accomplished after 16 weeks of therapy. Patients with systemic sclerosis and peripheral small vessel disease have limited therapeutic options. Treprostinil is a prostacyclin analogue that can be delivered by subcutaneous infusion and is approved in the USA only for treatment of primary pulmonary hypertension. This report provides an impressive example of an alternative, complementary indication for the use of treprostinil.

Comparing the guidelines: Anticoagulation therapy to optimize stroke prevention in patients with atrial fibrillationJOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGYRockson, S. G., Albers, G. W.2004; 43 (6): 929-935

Abstract

Atrial fibrillation (AF) is an important risk factor for stroke. According to a pooled analysis of controlled clinical trials with warfarin, anticoagulation therapy reduces stroke risk by 62%. However, clinicians must decide whether the benefit of long-term anticoagulation therapy with available agents outweighs the risk of bleeding for individual patients. Guidelines issued by the American College of Chest Physicians and by the joint American College of Cardiology, American Heart Association, and the European Society of Cardiology task force recommend antithrombotic therapy to protect AF patients from stroke based on risk-stratification algorithms. Risk factors for stroke AF patients include age > or =75 years; hypertension; thyrotoxicosis; diabetes; cardiovascular disease; congestive heart failure; and history of stroke, transient ischemic attack, or thromboembolism. Patients at high risk for stroke experience greater absolute benefit from anticoagulation therapy than patients at low risk. The guidelines are consistent in recommendations for high-risk patients (warfarin therapy, international normalized ratio 2.0 to 3.0) and low-risk patients (aspirin 325 mg), but differ for intermediate-risk patients with diabetes or heart disease. The guidelines continue to evolve, and future guidelines are likely to incorporate new clinical data, including the CHADS(2) algorithm for determining risk and the results of the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial, the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation study, and the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation II to V trials.

Abstract

Percutaneous coronary interventions represent an attractive alternative to surgical revascularization; nevertheless, these techniques continue to be characterized by their propensity to elicit restenosis. Despite an exhaustive search for an effective pharmacotherapy to treat or prevent restenosis, hundreds of clinical trials have failed to identify an agent with proven therapeutic benefit. Recently, however, the Food and Drug Administration approved intracoronary radiation (brachytherapy) as a viable therapeutic option for in-stent stenosis. In addition, recent randomized trials have shown encouraging results for drug-eluting stents. This article reviews the pathophysiology of restenosis, along with current and future treatment options.

Abstract

The vascular system is locally specialized to accommodate widely varying blood flow and pressure and the distinct needs of individual tissues. The endothelial cells (ECs) that line the lumens of blood and lymphatic vessels play an integral role in the regional specialization of vascular structure and physiology. However, our understanding of EC diversity is limited. To explore EC specialization on a global scale, we used DNA microarrays to determine the expression profile of 53 cultured ECs. We found that ECs from different blood vessels and microvascular ECs from different tissues have distinct and characteristic gene expression profiles. Pervasive differences in gene expression patterns distinguish the ECs of large vessels from microvascular ECs. We identified groups of genes characteristic of arterial and venous endothelium. Hey2, the human homologue of the zebrafish gene gridlock, was selectively expressed in arterial ECs and induced the expression of several arterial-specific genes. Several genes critical in the establishment of left/right asymmetry were expressed preferentially in venous ECs, suggesting coordination between vascular differentiation and body plan development. Tissue-specific expression patterns in different tissue microvascular ECs suggest they are distinct differentiated cell types that play roles in the local physiology of their respective organs and tissues.

Abstract

A growing body of evidence has demonstrated that oxidants play a critical role in the pathogenesis of endothelial dysfunction. Pathologic processes fundamental to development and progression of endothelial dysfunction such as the oxidation of LDL, the loss of bioavailable nitric oxide, and the vascular inflammatory response are all modulated by oxidant stress. Therapeutic strategies to reverse endothelial dysfunction have begun to focus on agents with the ability to ameliorate oxidant stress.Preclinical and clinical studies evaluating the actions of antioxidants as well as traditional cardiovascular therapies in ameliorating oxidative stress and endothelial dysfunction were reviewed through the use of a MEDLINE search of English language articles published between the years of 1992 and 2002.Antioxidants appear to be an attractive candidate therapy, yet despite compelling preclinical evidence supporting their benefits, efforts to validate the use of vitamins C and E in a clinical setting have been conflicting. In contrast, conventional cardiovascular therapies such as ACE inhibitors, statins, insulin-sensitizing agents, and estrogens have been shown to alleviate endothelial dysfunction, often independent of their effects on systemic disease processes.These agents restore endothelial function through their salutary effects on pathologic vascular oxidative processes.

Abstract

Lymphedema is the term commonly employed to describe the spectrum of pathological states that arise as a consequence of functional lymphatic insufficiency. These human disease entities currently lack an effective cure. Satisfactory therapeutic strategies for both primary and secondary lymphedema will require additional insight into the complex cellular mechanisms and responses that comprise both normal lymphatic function and its regional derangement in states of pathologic dysfunction. Such insights must, initially, be derived from suitable animal models of the chronic human disease process. Historically, efforts to replicate the untreated disease of human lymphedema in animals, through surgery, irradiation, and toxicology, have been fraught with difficulty. The major impediments to the creation of satisfactory animal models have included an inability to reproduce the chronic disease in a stable, reproducible format. Recently, with the promise of potentially successful growth factor-mediated therapeutic lymphangiogenesis, and with the enhanced availability of investigative tools to assess therapeutic responses to molecular therapies, there has been a resurgence of interest in the development of viable animal models of lymphatic insufficiency. Current research has led to the development of genetic and postsurgical models of lymphedema that closely simulate the human conditions of primary and secondary lymphatic insufficiency, respectively. Such models will help to refine the assessment of various therapeutic approaches and their potential applicability to human disease interventions.

Abstract

Lymphedema-edema that results from chronic lymphatic insufficiency-is a chronic debilitating disease that is frequently misdiagnosed, treated too late, or not treated at all. There are, however, effective therapies for lymphedema that can be implemented, particularly after the disorder is properly diagnosed and characterized with lymphoscintigraphy. On the basis of the lymphoscintigraphic image pattern, it is often possible to determine whether the limb swelling is due to lymphedema and, if so, whether compression garments, massage, or surgery is indicated. Effective use of lymphoscintigraphy to plan therapy requires an understanding of the pathophysiology of lymphedema and the influence of technical factors such as selection of the radiopharmaceutical, imaging times after injection, and patient activity after injection on the images. In addition to reviewing the anatomy and physiology of the lymphatic system, we review physiologic principles of lymphatic imaging with lymphoscintigraphy, discuss different qualitative and quantitative lymphoscintigraphic techniques and their clinical applications, and present clinical cases depicting typical lymphoscintigraphic findings.

Abstract

The efficient function of the immune system necessitates the complex interaction of antigens, antigen-presenting cells, and cell populations that modulate, regulate and effectuate the immune response. In order to overcome the spatial limitations that are imposed by the constraints of the system, the immune system has evolved a dependence upon the lymphatic vasculature to serve the biological needs of immune trafficking. This review will focus upon useful ex vivo and intact animal models that possess the ability to provide valuable information about leukocyte trafficking.

Abstract

Secondary lymphedema is a localized, acquired lymphatic microcirculatory disturbance that affects large numbers of patients after breast cancer therapy. There is a paucity of objective methods to quantitate lymphatic function and to anticipate the response to therapeutic interventions. We applied radionuclide lymphoscintigraphy to evaluate lymphatic transport and axillary lymph node visualization in women following breast cancer therapy to determine the utility of these data in these patients. Lymphoscintigraphy was performed after subcutaneous injection of 0.25 mCi of Tc-filtered sulfur colloid. Subcutaneous accumulation of radiotracer ('dermal backflow') and the visualization of axillary lymph nodes were graded using our own scoring system. The ratio of radioactivity within the affected to normal axillae (ARR) was also quantified. Nineteen patients with lymphedema after breast cancer therapy were evaluated. The disease severity was documented by serial measurements of the limb volume using the truncated cone formula. Responses to therapy were quantified after completion of the therapy. There was a correlation between the ARR and the percentage reduction in edema volume. The lymphoscintigraphic score correlated with the initial arm volume excess and with the durationof lymphedema. It can be concluded that quantitative and semi-quantitative assessment by radionuclide lymphoscintigraphy represents a potentially useful tool for the clinical assessment of upper extremity lymphedema.

Abstract

Disruption of the lymphatic circulation through breast carcinoma-associated axillary lymph node dissection, with or without radiation therapy, reportedly is the most common cause of lymphedema in developed countries. There is no cure for breast carcinoma-associated lymphedema. Although intermittent pneumatic compression (IPC) has been acknowledged as a potential component of the multidisciplinary therapeutic strategy in the treatment of patients with breast carcinoma-associated lymphedema, prospective study of its adjunctive safety and efficacy is required.IPC was assessed as a component of the initial therapeutic regimen for newly treated patients with breast carcinoma-associated lymphedema. Twenty-three patients who had not previously been treated for lymphedema were randomized to receive either decongestive lymphatic therapy (DLT) alone or DLT with daily adjunctive IPC. Patients with stable, treated, breast carcinoma-associated lymphedema also were assessed in the maintenance phase of therapy. Twenty-seven patients were randomized either to DLT alone or to DLT coupled with daily IPC. In both studies, objective assessment included serial measurement of volume by water displacement, tissue tonometry to assess elasticity of the skin, and goniometry to measure joint mobility.During initial treatment, the addition of IPC to standard DLT yielded an additional mean volume reduction (45.3% vs. 26%; P < 0.05). During maintenance DLT alone, there was a mean increase in volume (32.7 +/- 115.2 mL); with DLT and IPC, there was a mean volume reduction (89.5 +/- 195.5 mL; P < 0.05). In both studies, IPC was tolerated well without detectable adverse effects on skin elasticity or joint range of motion.When IPC is used adjunctively with other, established elements of DLT, it provides an enhancement of the therapeutic response. IPC is well tolerated and remarkably free of complications.

Abstract

Chronic regional impairments of the lymphatic circulation often lead to striking architectural abnormalities in the lymphedematous tissues. Lymphedema is a common, disabling disease that currently lacks a cure. Vascular endothelial growth factors C and D mediate lymphangiogenesis through the VEGFR-3 receptor on lymphatic endothelia. The purpose of this study was to investigate the therapeutic potential for lymphangiogenesis with VEGF-C. We developed a rabbit ear model to simulate human chronic postsurgical lymphatic insufficiency. Successful, sustained surgical ablation of the ear lymphatics was confirmed by water displacement volumetry. After complete healing, the experimental animals (n=8) received a single, s.c. 100 microg dose of VEGF-C in the operated ear; controls (n=8) received normal saline. Radionuclide lymphoscintigraphy was performed to quantitate lymphatic function. Immunohistochemistry (IHC) was performed 7-8 days following treatment. After VEGF-C, there was a quantifiable amelioration of lymphatic function. IHC confirmed a significant increase in lymphatic vascularity, along with reversal of the intense tissue hypercellularity of untreated lymphedema. This study confirms the capacity of a single dose of VEGF-C to induce therapeutic lymphangiogenesis in acquired lymphedema. In addition to improving lymphatic function and vascularity, VEGF-C can apparently reverse the abnormalities in tissue architecture that accompany chronic lymphatic insufficiency.

Abstract

The Hennekam syndrome is an infrequently reported heritable entity characterized by lymphedema, lymphangiectasia, and developmental delay. Here we add an additional 8 patients, and compare their findings to the 16 cases from the literature. The lymphedema is usually congenital, can be markedly asymmetrical, and, often, gradually progressive. Complications such as erysipelas are common. The lymphangiectasias are present in the intestines, but have also been found in the pleura, pericardium, thyroid gland, and kidney. Several patients have demonstrated congenital cardiac and blood vessel anomalies, pointing to a disturbance of angiogenesis in at least some of the patients. Facial features are variable, and are chiefly characterized, in a typical patient, by a flat face, flat and broad nasal bridge, and hypertelorism. Facial features are thought to mirror the extent of intrauterine facial lymphedema, or may be caused by lymphatic obstruction that affects the early migration of neural crest tissue. Other anomalies have included glaucoma, dental anomalies, hearing loss, and renal anomalies. The psychomotor development varies widely, even within a single family, from almost normal development to severe mental retardation. Convulsions are common. The existence of 10 familial cases, equal sex ratio, increased parental consanguinity rate (4/20 families), and absence of vertical transmission are consistent with an autosomal recessive pattern of inheritance. It seems likely that most (but not all) manifestations of the entity can be explained as sequences of impaired prenatal and postnatal lymphatic flow, suggesting that the causative gene(s) should have a major function in lymphangiogenesis.

Abstract

Although clinical manifestations of myocarditis in systemic lupus erythematosus are uncommon, noninvasive cardiac testing may detect subclinical cases. The pathogenesis of myocarditis in systemic lupus erythematosus has been ascribed to many factors, including autoimmunity, medications, and coexisting diseases. Lupus myocarditis merits urgent clinical attention because of the likely progression to arrhythmias, conduction disturbances and heart block, dilated cardiomyopathy, and heart failure. Endomyocardial biopsy can be used to identify the underlying inflammatory histopathology. Usual therapy includes high-dose corticosteroids, in addition to standard cardiac medications.

Abstract

It has been proposed that concomitant iatrogenic venous obstruction substantially contributes to the appearance and severity of the secondary lymphedema that follows cancer surgery, radiation, and other traumas. The purpose of this study was to investigate the frequency of venous obstruction in the clinical presentation of patients with secondary lymphedema and to analyze the efficacy of interventional therapy in this patient population.The experience of the university center for lymphatic and venous disorders with combined lymphaticovenous edema was retrospectively examined. The records and clinical course were reviewed for all patients referred to a university lymphedema center for evaluation between January 1996 and March 1999. During this interval, in 365 patients with lymphedema, 35 radiocontrast venograms were obtained to evaluate the suspected presence of mixed lymphaticovenous edema. Venographic evidence of venous stenosis (>50%) or occlusion was analyzed, as were the technical success of the intervention, determined by ability to cross the affected segment of the vein and perform venoplasty and place the stent, and the clinical success of the intervention assessed by relief of clinical symptoms (edema, pain) within 24 hours.The diagnosis of venous obstruction was confirmed in 17 patients (4.6% of all patients with lymphedema; 49% of patients studied with venography). Venography disclosed clinically relevant venous stenosis in five of seven patients with edema of the upper extremity and in six of 10 patients with leg lymphedema. Venous occlusion was found in two of seven patients with upper extremity edema and in four of 10 patients with leg lymphedema. Percutaneous endovascular venoplasty was attempted in all 17 patients and was successful in 16. Subsequent venous stent placement was performed in three patients with upper extremity edema and in all patients with lower extremity lymphedema. Clinical amelioration of edema was observed in 15 of these 17 patients. Amelioration was assessed by relief of symptoms, improvement in function, and reduction in limb girth.This study supports the clinical importance of concomitant venous obstruction in some patients with chronic secondary lymphedema. Edema can often be ameliorated through percutaneous catheter-based interventions.

Abstract

The human disease states that are characterized by functional lymphatic insufficiency currently lack a cure. Molecular approaches may ultimately provide a therapeutic window to reverse the stigmata of both primary and secondary lymphatic insufficiency. To harness the potential therapeutic power of lymphangiogenesis, testing the safety and efficacy of the treatment response will be necessary. This, in turn, necessitates the availability of suitable preclinical animal models of the disease processes in question, along with suitable research tools to permit an assessment of the response to applied therapies. An ideal model would reproducibly and inexpensively replicate the untreated disease of human lymphedema. It would closely simulate the biology, as we understand it, of the human disease, and would replicate both the pathogenesis of the disease, including its natural history and the temporal patterns of its clinical expression. In this way, one might aspire to make valid predictions about the human applicability of therapy by extrapolation from observations in animal models. In addition to the availability of suitable animal models, the required investigative tools must also be available. In the context of lymphangiogenesis, to assess the therapeutic response, one must certainly possess the ability to recognize newly developed lymphatic vasculature. Sophisticated immunohistochemical and imaging techniques make this increasingly feasible. Initial experimental observations indicate that growth factor and gene therapy with VEGF-C holds promise for the treatment of both primary and secondary forms of lymphedema.

Abstract

A growing body of experimental evidence supports the pivotal role of chemokines in the pathogenesis of vascular disease. The endothelial expression of monocyte chemoattractant protein-1 (MCP-1) is apparently essential for the earliest cellular responses of atherogenesis. Many atherogenic and anti-atherogenic stimuli can be construed to exert their effects predominantly upon MCP-1 expression within the vascular wall. The atherogenic effects of interleukin-8 (IL-8) seem to be mediated through the down-regulation of the tissue inhibitor of metalloproteinase-1 (TIMP-1). Biological expression of these two important vascular chemokines is further modulated by NF-kappaB. The delineation of these molecular forces that drive atherogenesis increasingly underscores the pivotal role of various chemokines. It is anticipated that more precise delineation of these patterns of gene expression will help to identify molecular targets for the prevention and treatment of atherosclerosis.

Abstract

Prevailing hospital practice dictates a protracted phase of observation for patients with chest pain to establish or exclude the diagnosis of myocardial infarction. Early diagnosis of acute myocardial infarction may improve patient care and reduce both complications and hospital costs. A study was performed to investigate the feasibility of early diagnosis of myocardial infarction within the first 9 hours of the hospital stay.The records of all patients admitted with chest pain within one calendar year were analyzed. The timing of creatine kinase-MB (CK-MB) quantification was determined with reference to the initial phlebotomy (time 0). An enzymatic diagnosis of myocardial infarction was assigned if any determination of CK-MB exceeded the upper limit of normal, and the diagnosis of each patient at or before 9 hours (early diagnosis) was compared to the ultimate diagnosis at 14 to 24 hours (final diagnosis) beyond initial assessment.Of the 528 included patients, 523 patients (99.1%) had identical early and final diagnostic outcomes; 5 patients (0.9%) had conflicting results. An early diagnosis of myocardial infarction was assigned to 195 of the 528 patients (36.9%). Of these, 190 achieved the diagnosis within 9 hours (sensitivity 97.4%). The negative predictive value was 98.5%.Standard CK-MB mass measurements within 9 hours of arrival provided an accurate clinical assessment in > 99% of the cases. The high sensitivity and negative predictive values suggest that early diagnosis of myocardial infarction is feasible and reliable.

Abstract

Extensive animal studies and a growing number of human clinical trials have now definitively demonstrated the central role of the renin-angiotensin-aldosterone system in the expression and modulation of cardiovascular disease. In contrast to the original hypothesis, the benefits of angiotensin antagonism do not emanate from the antihypertensive effect alone. Subsequent extensive investigations of angiotensin blockade suggest that the benefits of this approach may also result from the pharmacologic alteration of endothelial cell function and the ensuing changes in the biology of the vasculature. The more recent availability of direct antagonists of the AT(1) angiotensin receptor has introduced an element of doubt into this realm of clinical decision making. The receptor antagonists and the more widely studied converting-enzyme inhibitors share many endpoint attributes. Nevertheless, the partially overlapping mechanisms of action for the two classes of angiotensin antagonists confer distinct pharmacologic properties, including side effect profiles, mechanisms of action, and theoretic salutary effects upon the expression of cardiovascular disease. The current review will attempt to contrast the biology of angiotensin converting-enzyme inhibition with angiotensin II receptor antagonism. A discussion of the differential effects of these drug classes on endothelial cell function and on the modulation of vascular disease will be utilized to provide a theoretic framework for clinical decision making and therapeutics.

Abstract

Lymphedema is a set of pathologic conditions that are characterized by the regional accumulation of excessive amounts of interstitial protein-rich fluid. These occur as a result of an imbalance between the demand for lymphatic flow and the capacity of the lymphatic circulation. Lymphedema can result from either primary or acquired (secondary) disorders. In this review, the pathophysiology, classification, natural history, differential diagnosis, and treatment of lymphedema are discussed.

Abstract

In photoangioplasty, light activation of a photosensitive drug offers the potential for treatment of long segments of vascular disease. This is a brief description of a study designed to evaluate the safety and tolerability of a new photosensitizer, Antrin (motexafin lutetium), in the endovascular treatment of atherosclerosis.An open-label, single-dose, escalating drug- and light-dose study was performed in patients with atherosclerotic peripheral arterial insufficiency. Clinical evaluation, serial quantitative angiography, and intravascular ultrasonography were performed. Therapy was well tolerated, and only minor side effects were observed. Treatment produced no deleterious vascular effects. Although this study was not designed to examine clinical efficacy, several secondary end points suggested a favorable therapeutic effect.This phase I study demonstrates that photoangioplasty with motexafin lutetium is well tolerated and safe. Preliminary efficacy data suggest a future role for the treatment of flow-limiting atherosclerosis.

Abstract

A prospective evaluation was undertaken to assess the efficacy of intensive, short-term decongestive lymphatic therapy coupled with focused patient instruction in long-term self-care for the management of lymphedema.The therapeutic responses of 79 patients with lymphedema were analyzed prospectively. Each patient received intensive, short-term decongestive lymphatic therapy, with quantification of the extent and durability of the clinical response. Decongestive lymphatic therapy was performed by therapists trained in these techniques. The mean (+/-SD) duration of therapy was 8+/-3 days. Instruction in self-management techniques was incorporated into the therapeutic regimen by day 3 of the patient's treatment. The mean period of follow-up was 38+/-52 days. Changes in the volume of the affected limb were assessed with a geometric approximation derived from serial measurements of circumference along the axis of the limb.The mean short-term reduction in limb volume was 44%+/-62% of the excess volume in the upper extremities and 42%+/-40% in the lower extremities. At follow-up, these results were adequately sustained: mean long-term excess volume reductions of 38%+/-56% (upper extremities) and 41%+/-27% (lower extremities) were observed.Decongestive lymphatic therapy, combined with long-term self-management, is efficacious in treating patients with lymphedema of the extremity.

Abstract

Photodynamic therapy (PDT) has been studied and applied to various disease processes. The potential of PDT for selective destruction of target tissues is especially appealing in cardiovascular disease, in which other existing interventional tools are somewhat nonselective and carry substantial risk of damage to the normal arterial wall. Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic and, potentially, restenotic lesions) is fueled by more effective second-generation photosensitizers and technological advances in endovascular light delivery. This excitement revolves around at least 4 significant attributes of light-activated therapy: the putative selectivity and safety of photoangioplasty, the potential for atraumatic and effective debulking of atheromatous plaque through a biological mechanism, the postulated capability to reduce or inhibit restenosis, and the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions. The available nonclinical data, coupled with the observations of a new phase I trial in human peripheral atherosclerosis, suggest a promising future for photoangioplasty in the treatment of primary atherosclerosis and prevention of restenosis.

Abstract

Aggressively applied decongestive measures (eg, manual lymphatic drainage, low-stretch bandaging, exercise, skin care, application of compressive elastic garments) are the mainstay of lymphatic therapy. Therapeutic regimens should differentiate between the goals of acute volume reduction and the maintenance of limb volume. Elastic garments should not be employed until maximal volume reduction has been attained through decongestive lymphatic techniques. It is my opinion that use of intermittent pneumatic compression devices can play an important adjunctive role to decongestive lymphatic therapy but should not be substituted for these techniques. At this time, I am not inclined to use pharmacologic therapy in these patients but anxiously await the results of studies that might demonstrate efficacy for molecular approaches. Surgical intervention is reserved for a small number of well-selected patients. Liposuction for volume reduction appears to be a very promising approach for specific patients.

Abstract

Coronary heart disease remains the leading cause of death in the United States. Although coronary heart disease and stroke entail very expensive therapies and extensive hospital utilization, the cost of preventive measures is also quite expensive. In this review, the factors that determine the cost-effectiveness of statin therapy for the primary and secondary prevention of coronary heart disease are discussed. A risk-based strategy for the selection of patients seems to provide cost-effective utilization of this potent treatment strategy. Appropriate patient selection should be accompanied by aggressive measures to improve utilization and compliance through improved physician and patient education.

Abstract

Hennekam syndrome is a rare, recently described genetic disorder in which facial anomalies and mental retardation accompany congenital lymphedema and intestinal lymphangiectasia. Several other somatic abnormalities have variously been described, as have milder degrees of lymphatic dysfunction. The authors herein describe a case of Hennekam syndrome in which the diagnostic difficulties were partially overcome by the judicious use of radionuclide scintigraphy to verify the lymphedematous component of the patient's presentation.

Abstract

In an attempt to avert impending, primary amputation, an 85-year-old woman with chronic critical leg ischemia was enrolled in an experimental protocol to induce therapeutic angiogenesis. Treatment consisted of six consecutive, weekly intravenous infusions of recombinant basic fibroblast growth factor (bFGF). Angiographic evaluation was performed before and after therapy. The patient's clinical response was monitored through serial measurements of the ankle/brachial index and by repetitive assessment of limb flow by mercury strain-gauge plethysmography. A beneficial clinical response was detectable by week 4 of therapy, which was characterized by an improved walking distance, relief of ischemic pain, a marked reduction in analgesic consumption, and healing of persistent, unresponsive, painful inflammation of the hallux. The clinical improvement was sustained throughout the remaining weeks of therapy and follow-up evaluation. Plethysmography documented improved blood flow; specifically, the augmentation of digital flow was sustained and correlated with the marked improvement in the patient's clinical status.

Abstract

Lymphedema is an all too common occurrence following breast carcinoma therapy. Despite its prevalence, the predisposing factors to the development of this secondary form of lymphedema remain poorly understood.Several studies have addressed these questions and are reviewed here.Treatment factors that appear to predispose to the late, subjective appearance of lymphedema include the extent of axillary surgery and exposure to high dose axillary radiotherapy, particularly when combined with surgical clearance of the axilla. Other pertinent patient factors may include the presence of hypertension and exposure to airline travel. Clinical features unrelated to the risk of lymphedema development include patient age; drug therapy; time interval to presentation, surgery, or radiotherapy to the breast; total dose of radiation; and menopausal status. The potential importance of concomitant venous abnormalities in these patients is worthy of consideration.Breast carcinoma-related secondary lymphedema is an important subjective and functional problem for affected patients. Additional research into the predisposing factors to this common problem is likely to foster enhanced patient education and to produce more efficacious measures to control this disease.

Abstract

The functional significance of coronary-cameral fistulae, and the effect of these arterial anomalies upon effective coronary blood flow, continue to be debated. Two cases of coronary cameral fistulae, each of which illustrates the likelihood of an ischemic substrate, are herein presented, along with a review of the relevant literature regarding this disorder.

Abstract

This review presents the diagnostic features, the pathophysiology and the available therapies for lymphedema. This disease is often able to be diagnosed by its characteristic clinical presentation, yet, in some cases, ancillary tests might be necessary to establish the diagnosis, particularly in the early stages of the disease and in edemas of mixed etiology. These diagnostic modalities are also useful in clinical studies. Available modalities include isotopic lymphoscintigraphy, indirect and direct lymphography, magnetic resonance imaging, computed tomography and ultrasonography. Lymphedema may be primary or secondary to the presence of other disease and/or to the consequences of surgery. Primary lymphedema may occur at any phase of life but it most commonly appears at puberty. Secondary lymphedema is encountered more often. The most prevalent worldwide cause of lymphedema is filariasis, which is particularly common in south-east Asia. In the USA, postsurgical lymphedema of the extremity prevails. Complications of chronic limb lymphedema include recurrent cellulitis and lymphangiosarcoma. Most patients are treated conservatively, by means of various forms of compression therapy, including complex physical therapy, pneumatic pumps and compressive garments. Volume reducing surgery is performed rarely. Lymphatic microsurgery is still in an experimental stage, although a few centers consistently report favorable outcomes.

Abstract

The authors review the current understanding of lymphatic anatomy and physiology, and the pathophysiology of lymphedema. The skin lymphatic system consists of the initial lymphatics, which converge into lymphatic precollectors, collectors and lymphatic ducts; these in turn convey the lymph to the regional lymph nodes. Interstitial fluid and particles enter the initial lymphatics through interendothelial openings and by vesicular transport. Lymphatic uptake is enhanced by external compression. Lymphatic transport depends greatly on contraction of lymphangions, which generate the suction force that promotes absorption of interstitial fluid and expels lymph to collecting ducts. In lymphedema, various types of congenital and acquired abnormalities of lymphatic vessels and lymph nodes have been observed. These often lead to lymphatic hypertension, valvular insufficiency and lymphostasis. Accumulation of interstitial and lymphatic fluid within the skin and subcutaneous tissue stimulates fibroblasts, keratinocytes and adipocytes eventuating in the deposition of collagen and glycosaminoglycans within the skin and subcutaneous tissue together with skin hypertrophy and destruction of elastic fibers.

Abstract

Lymphorrhea is a rarely described complication of chronic lymphedema, in which the disrupted flow through diseased lymphatic channels gives rise to the external drainage of lymph, often heralded by the presence of an enlarging lymphocele. This report documents the applicability of the Reid sleeve, a novel, conservative form of therapy, in an unusually severe and protracted example of lymphorrhea.

Abstract

Group B streptococci commonly colonize parturient women, yet pregnancy-associated endocarditis due to this organism is rare. Most reports of group B streptococcal endocarditis are from the preantibiotic era and occurred in women with rheumatic mitral valve disease. Reported herein are two cases of fatal group B streptococcal endocarditis involving the aortic valve of women with no preexisting heart disease. One had undergone a second-trimester abortion and the other had a normal pregnancy and uncomplicated vaginal delivery.

Abstract

Antialprenolol rabbit antibodies were fractionated on an acebutolol affinity resin, followed by L-propranolol elution so as to separate a class of binding sites that mimic the beta-adrenergic receptor. Allotype-identicaL rabbits were immunized with this fraction. After 6 mo, antisera exhibited antiidiotypic activity inhibiting [3H]alprenolol binding to the original antibody and to rabbit antiacebutolol antibodies, which had a spectrum of ligand-binding properties identical to the original idiotype. Those antisera demonstrating the original idiotype. Those antisera demonstrating the most potent antiidiotypic activity also blocked [3H]alprenolol binding to the beta-adrenergic receptor of turkey membrane, canine pulmonary membrane, and rat reticulocyte. An idiotype affinity-purified fraction showed similar activity, inhibiting beta-receptor binding with a calculated dissociation constant (KD) of 53 nM. Isoproterenol-mediated adenylate cyclase activity was also inhibited in a competitive manner. The universality of recognition of these antiidiotypic antisera indicate that the three-dimensional structure of a receptor's binding site can be modeled by a subset of an elicited antibody population.

Abstract

The myocardial responsiveness of conscious, instrumental dogs to exogenously administered isoproterenol and norepinephrine was investigated in neonatal, 6-wk-old, and adult animals. Comparable base-line values for peak left ventricular derivative of pressure with respect to time were observed in all age categories. However, when compared with adult responses, the sympathomimetic amine-induced increases in neonatal left ventricular dP/dt were significantly blunted at each concentration of adrenergic agonist examined, whereas the 6-wk-old puppies displayed an intermediate inotropic response. To investigate the cellular mechanisms of this blunted neonatal response, we correlated physiologic and biochemical measurements of the myocardial responses to catecholamines in each age category. When compared with adult myocardial membrane preparations, neonatal cardiac membranes were characterized in vitro by an increased density of beta-adrenergic binding sites, comparable affinity for adrenergic agonists and antagonists, and an enhanced coupling of adenylate cyclase activation to receptor occupancy. Simultaneous changes in either the serum catecholamine concentration or the membrane content of other intrinsic proteins failed to account for the observed neonatal increase in beta-adrenergic receptor density. These findings are most consistent with a compensatory mechanism of the cardiac cell membrane, whereby an inherent depression in the adrenergic responsiveness of the immature myocardium appears to induce the increase in receptor density and activation of adenylate cyclase.

Abstract

We immunized rabbits with an antigen prepared by covalent linkage of alprenolol, a beta-adrenergic receptor antagonist, to bovine serum albumin. Competitive inhibition of [3H]dihydroalprenolol binding to antisera with a variety of unlabeled ligands revealed broad antibody specificity for beta-adrenergic antagonists and agonists. The antiserum was subjected to affintiy fractionation on hydroxybenzylpindolol-Sepharose 4B. Successive elution with 100 mM Tris HCl, 1M NaCl, 4 M LiBr, and 5 M guanidine yielded fractions with increasing affintiy for hydroxybenzylpindolol. The ligand-binding properties of these affinity-fractionated antibodies suggest that certain of these fractions recognize structural aspects of individual beta-adrenergic ligands which are irrelevant to their biological activity, whereas others can be used to distinguish shared functional properties, such as the ethanolamine side chain, within the structural heterogeneity of beta-adrenergic drugs. In particular, elution of hydroxybenzylpindolol-adsorbed antibody with (-)-propranolol allowed identification of an antibody fraction specific for the (-)-stereoisomer. Thus, affinity fractionation of antibodies raised against beta-adrenergic ligands can provide useful analogues for the further study of the recognition properties of the beta-adrenergic receptor.

Abstract

An atypical case of neuroblastoma is described, in which the diagnosis was facilitated by the application of a new biochemical procedure, the assay of plasma dopamine-beta-hydroxylase activity. This laboratory tool is proposed as a useful adjunct to established techniques in the diagnosis of neural crest tumors.

Abstract

A prospective study was undertaken to evaluate the relative contribution of changes in sympathetic nervous system activity, as reflected by changes in dopamine-beta-hydroxylase (DBH) activity, to the pathogenesis of oral contraceptive-induced hypertension. Precontraceptive and serial post contraceptive determinations of blood pressure, plasma renin activity (PRA), DBH activity, and changes in body weight were obtained in twelve control patients and forty-one oral contraceptive users. Forty-four percent of oral contraceptive users had increases in blood pressure but remained normotensive and 17% became frankly hypertensive. The precontraceptive and average post contraceptive levels of mean arterial pressure (MAP), PRA and DBH activity in each patient were compared using paired group analysis. Control patients (group I) exhibited no significant changes in these variables, while the patients with contraceptive-induced increases in MAP (groups III and IV) underwent significant, parallel increases in DBH activity. Finally, the linear regression of changes in MAP on the percent change in DBH activity was examined. The positive slopes in groups III and IV differed significantly from the negative slope of the controls (group I). The data have been interpreted to reflect an inappropriate oral contraceptive-induced stimulus to sympathetic nervous system activity, leading to increases in MAP in susceptible individuals.

Abstract

Subjects with the Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase deficiency with self-mutilation) exhibit an apparently unique pattern of adrenergic dysfunction characterized by elevated plasma dopamine beta-hydroxylase activity and an absence of pressor response to acute sympathetic stimulation. Patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase without self-mutilation do not exhibit these abnormalities of adrenergic function.